In the last century, antibiotics were developed that led to significant reductions in mortality. Unfortunately, widespread use has led to the rise of antibiotic resistant bacteria, e.g., methicillin resistant Staphyloccocus aureus (MRS A), vancomycin resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumonias (PRSP). Some bacteria are resistant to a range of antibiotics, e.g., strains of Mycobacterium tuberculosis resist isoniazid, rifampin, ethambutol, streptomycin, ethionamide, kanamycin, and rifabutin. In addition to resistance, global travel has spread relatively unknown bacteria from isolated areas to new populations. Furthermore, there is the threat of bacteria as biological weapons. These bacteria may not be easily treated with existing antibiotics.
Infectious bacteria employ the coenzyme A (CoA) biosynthesis pathway, and, particularly in the penultimate step of the pathway, depend on phosphopantetheine adenyl transferase (PPAT), which transfers an adenyl moiety from adenosine triphosphate (ATP) to 4′-phosphopanthetheine, forming dephospho-CoA (dPCoA). While PPAT is present in mammalian cells, bacterial and mammalian PPAT enzymes differ substantially in primary sequence (about 18% identity) and physical properties. Thus, PPAT presents a desirable, selective target for new antibiotics.
Recent efforts have resulted in the identification of compounds which inhibit E. coli PPAT (Leslie, et al. “Antibacterial Anthranilates with a Novel Mode of Action”; Zhao, et al. “Inhibitors of Phosphopantetheine Adenylyltransferase”; Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Diego, Calif., 2002). However, these compounds are not appropriate for drug development. Furthermore, in one case, the structures are peptidic, while in the other case, representative compounds exhibited poor activity against purified PPAT.
Therefore, there is a need for new antibiotics that target PPAT, whereby infections from bacteria dependent on PPAT can be treated.